Boron-10 containing biocompatible nanostructures

ABSTRACT

A method comprises providing a plurality of nanostructures comprising a base material. The plurality of nanostructures are exposed to a first material at a first deposition temperature. The plurality of nanoparticles are exposed to a second material at a second deposition temperature, and exposed to a Boron-10 (10B) containing material at a third deposition temperature so as to form a 10B-metal oxide based composite nanostructure.

STATEMENT OF GOVERNMENT INTEREST

This invention was made with government support under Contract No.DE-AC02-06CH11357 awarded by the United States Department of Energy toUChicago Argonne, LLC, operator of Argonne National Laboratory. Thegovernment has certain rights in the invention.

TECHNICAL FIELD

The present disclosure relates generally to the field of Boron-10 (¹⁰B)containing composite nanostructures formed using Atomic Layer Deposition(ALD).

BACKGROUND

Boron neutron capture therapy (BNCT) is a binary method for thetreatment of cancer, which is based on the nuclear reaction betweenboron atoms and low-energy thermal neutrons. In the naturally occurringstate, elemental boron has two stable isotopes, namely boron-10 (¹⁰B)and boron-11 (¹¹B). The more abundant isotope is ¹¹B (around 80%),however, the most distinguishing property of ¹⁰B is its high neutroncapture cross section for thermal neutrons (also called as slowneutrons). Hence, the reaction of a neutron with ¹⁰B yields two chargedparticles, a ⁴He nucleus and a ⁷Li nucleus, each of which is able tokill tumor cells due to their high linear energy transfer. Forsuccessful BNCT, a minimum of 20-30 μg of nonradioactive ¹⁰B per gram oftumor tissue is generally used. Another factor for the success of BNCTis the selective delivery of high amounts of boronated compounds totumor cells, while at the same time, the boron concentration in thecells of surrounding normal tissue should be kept low to minimize thedamage to normal tissue.

Further BNCT has been under study in cancer research to offer a muchmore targeted therapy compared to existing chemo or radiotherapy. Thesuccess of BNCT strongly depends on the improvement of the selectivityof boron-labeled compounds for cancer tissues (at least 20 ppm ¹⁰B inthe tumor is desirable) in order to establish a sufficient dose ratiobetween tumor cells, and healthy tissues (at least 3:1), e.g., bloodvessels and normal brain cells, during a sufficient time span. Inaddition to that, a high neutron flux density of about 10⁹ neutrons/scm² is desirable. The attainable absolute concentration and enrichmentof ¹⁰B in tumor cells strongly depends on the method of application andin the studies performed so far, ¹⁰B levels only reached the minimumvalues necessary for this kind of tumor therapy. In spite of allefforts, a more effective boron delivery agent is highly desirable inorder to perform targeted and reliable BNCT delivery to tumorous andcancerous cells.

SUMMARY

Embodiments described herein relate generally to compositenanostructures including ¹⁰B, methods of forming such compositenanostructures using ALD, and using such composite nanostructures fortreating cancer.

In some embodiments, a method comprises providing a plurality ofnanostructures comprising a base material; exposing the plurality ofnanostructures to a first material at a first deposition temperature;exposing the plurality of nanostructures to a second material at asecond deposition temperature; and exposing the plurality ofnanostructures to a 10-Boron (¹⁰B) containing material at a thirddeposition temperature so as to form a ¹⁰B-metal oxide-based compositenanostructure.

In some embodiments, a composite nanostructure comprises a first layerforming a core of the composite nanostructure, the first layercomprising a base material. A second layer of a ¹⁰B-metal oxidecomposite is deposited on the first layer.

In some embodiments, a method of treating cancer comprises injecting aplurality of composite nanostructures comprising ¹⁰B-metaloxide-magnetic material into a blood stream of a patient having cancercells. A magnetic field is generated in a vicinity of the cancer cellsso as to accumulate at least a portion of the plurality of compositenanostructures in the vicinity of the cancer cells. At least the portionof the plurality of composite nanostructures is irradiated with a streamof epithermal neutrons.

It should be appreciated that all combinations of the foregoing conceptsand additional concepts discussed in greater detail below (provided suchconcepts are not mutually inconsistent) are contemplated as being partof the inventive subject matter disclosed herein. In particular, allcombinations of claimed subject matter appearing at the end of thisdisclosure are contemplated as being part of the inventive subjectmatter disclosed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features of the present disclosure will becomemore fully apparent from the following description and appended claims,taken in conjunction with the accompanying drawings. Understanding thatthese drawings depict only several implementations in accordance withthe disclosure and are therefore, not to be considered limiting of itsscope, the disclosure will be described with additional specificity anddetail through use of the accompanying drawings.

FIG. 1 is schematic flow diagram of a method for fabricating compositenanostructures including ¹⁰B, according to an embodiment.

FIG. 2 is a schematic illustration of a ¹⁰B-metal oxide-base materialcomposite nanostructure, according to an embodiment.

FIG. 3 is a schematic flow diagram of a method for treating cancer using¹⁰B-metal oxide-magnetic material composite nanostructure, according toan embodiment.

FIG. 4 shows a plot of Quartz Crystal Microbalance (QCM) measurements ofmass deposition using ALD cycles of trimethyl aluminum (TMA), H₂O, and¹⁰Boric Acid-Methanol (¹⁰BA-Methanol) as a boron containing material toform a ¹⁰B—AlO composite structure.

FIG. 5 shows a plot of QCM measurements of mass deposition using ALDcycles to form ¹⁰B—AlO—Si composite micropillars using trimethylaluminum (TMA), H₂O, and ¹⁰B containing Trimethyl Borate (TMB); insetshows a scanning electron microscopy (SEM) image of the ¹⁰B—AlO—Simicropillars.

FIG. 6A is an optical image of Al₂O₃ nanoparticles; FIGS. 6B, 6C and 6Dare optical images of the Al₂O₃ nanoparticles coated with iron oxideusing progressive ALD cycles of ferrocene (Fe(Cp)₂) and O₃.

FIGS. 7A-7L are SEM images at various magnifications of the Fe₂O₃ coatedAl₂O₃ nanoparticles formed using ALD.

FIG. 8A is a X-ray Photon Spectroscopy (XPS) plot showing composition ofcommercially available Fe₂O₃ nanoparticles, and FIG. 8B is an XPS plotof composition of ¹⁰B—AlO—Fe₂O₃ composite nanostructures formed from thecommercially available Fe₂O₃ nanoparticles using ALD.

FIG. 9A is an XPS plot in the Boron spectrum of the commerciallyavailable Fe₂O₃ nanoparticles, and FIG. 9B is an XPS plot in the Boronspectrum of the ¹⁰B—AlO—Fe₂O₃ composite nanostructures.

FIG. 10 is an optical image of ¹⁰B—AlO—Fe₂O₃ composite nanostructures.

FIGS. 11A, 11B and 11C are XPS scans in the aluminum, boron and oxygenspectrums, respectively of the ¹⁰B—AlO—Si composite nanostructures.

FIGS. 12A, 12B, 12C and 12D are XPS scans in the aluminum, boron, oxygenand iron spectrums, respectively of the ¹⁰B—AlO—Fe₂O₃ compositenanostructures of FIG. 10.

Reference is made to the accompanying drawings throughout the followingdetailed description. In the drawings, similar symbols typicallyidentify similar components, unless context dictates otherwise. Theillustrative implementations described in the detailed description,drawings, and claims are not meant to be limiting. Other implementationsmay be utilized, and other changes may be made, without departing fromthe spirit or scope of the subject matter presented here. It will bereadily understood that the aspects of the present disclosure, asgenerally described herein, and illustrated in the figures, can bearranged, substituted, combined, and designed in a wide variety ofdifferent configurations, all of which are explicitly contemplated andmade part of this disclosure.

DETAILED DESCRIPTION

Embodiments described herein relate generally to compositenanostructures including ¹⁰B, methods of forming such compositenanostructures using ALD, and using such composite nanostructures fortreating cancer.

Boron neutron capture therapy (BNCT) is a binary method for thetreatment of cancer, which is based on the nuclear reaction betweenboron atoms and low-energy thermal neutrons. A promising strategy fortargeted delivery of boron to tumorous or cancerous tissues is the useof magnetically directed nanoparticles. The concept of Magnetic DrugTargeting (MDT), an efficient tumor treatment strategy, impliesintra-arterially administered superparamagnetic iron oxide nanoparticles(SPIONs), which are attracted by an external magnetic field that isdirected to the tumor tissue. However, fabrication of stable ¹⁰Bcontaining magnetic nanoparticles using conventional processes isdifficult.

Embodiments described herein relate to a method to create isotopicallypure ¹⁰B containing composite layers which can be added on tonanoparticle (e.g., biocompatible nanoparticles) substrates to form ¹⁰Bcomposite nanostructures. For example, ¹⁰B-metal oxide nanocompositescan be deposited on a nanoparticle based base material template such asFe₂O₃, Al₂O₃, TiO₂, SiO₂, Au, fullerenes etc., or soft biocompatiblepolymeric material and/or biocompatible magnetic materials (e.g., FeO orFe₂O₃ etc.).

Various embodiments of the ¹⁰B-metal oxide-base material compositenanostructures and methods to form such nanostructures may provide oneor more benefits including, for example: (1) allowing precise control ofloading of ¹⁰B in the nanostructures; (2) allowing fabrication ofnanostructures using a low cost and easily scalable ALD process; (3)providing fabrication of uniform and conformal coatings of ¹⁰B-metaloxide on the base material; (4) allowing fabrication at temperatures aslow as room temperature; (5) allowing fabrication of biocompatiblenanostructures that can be inserted safely in an animal or human bodyand be used as a therapeutic agent such as in cancer treatment.

FIG. 1 is a schematic flow diagram of a method 100 for fabricating aboron containing composite nanostructure such as a boron-metaloxide-base material composite nanostructure, according to an embodiment.The method 100 includes providing a plurality of nanostructuresincluding a base material, at 102. The nanostructures may have anysuitable size range, for example, in a range of 5-500 nm, inclusive ofall ranges and values therebetween. The base material may include, forexample, Al₂O₃, Fe₂O₃, ZrO₂, SiO₂, organically modified silica(ORMOSIL), TiO₂, MgO, CaF₂, ZnO, Au, Ag, graphene, graphene oxide, NaClor KCl. In various embodiments, the base material may be a biocompatiblematerial, for example, any of the base materials described herein. Insome embodiments, the base material may include a polymer (e.g., abiocompatible polymer such as a biodegradable polymer) which is capableof withstanding high temperature deposition (e.g., in a range of 50-200degrees Celsius) of a ¹⁰B containing composite thereon. Such polymersmay include, for example, polyamides, polycarbonates, polyurethanes,poly(glycolic acid), polylactides, poly(a-esters), poly(ethyleneglycol), poly(lactide-co-glycolide), polyhydroxyalkanoates,polycaprolactones, polypropylene fumarate, polyanhidrides, polyacetals,poly(ortho esters), polycarbonates, polyphosphazenes, polyphosphoesters,polyethers, etc. In particular embodiments, the base material mayinclude a magnetic material (e.g., FeO or Fe₂O₃).

In some embodiment, the plurality of nanostructures may be formedentirely of the base material. In some embodiments, the plurality ofnanostructures including the base material may be formed using an ALDprocess or any other suitable deposition process and may include asubstrate material having a layer of the base material disposed thereon.For example, a plurality of nanoparticles may be provided as asubstrate, and the base material grown on a surface thereof via ALD,chemical vapor deposition (CVD), metal oxide CVD (MOCVD), plasmaenhanced CVD (PECVD), sputtering, e-beam evaporation or any othersuitable deposition process so as to form the plurality ofnanostructures.

In some embodiments, the base material may be grown on the substratematerial via ALD which may be performed in a reaction chamber. ALDprocesses often comprise two half-reactions, whereby precursor materialsfor each half-reaction are kept separated throughout the coatingprocess. ALD material growth is based on self-limiting surfacereactions, which makes achieving atomic scale deposition controlpossible. In a first half-reaction, a precursor gas is introduced to asubstrate surface and produces a first monolayer. Excess or unreactedspecies and/or reaction by-product from the first half-reaction may bepurged from the substrate surface by flow of inert gas (i.e. nitrogen,argon, etc.), vacuum evacuation, by moving the substrate into a zone ofpure inert gas (i.e. spatial ALD) or other similar removal techniques. Asecond precursor of gas is then introduced to the substrate surface andreacts with the first monolayer to produce a monolayer on the substratesurface (i.e., the surface of the plurality of nanoparticles). Excess orunreacted species and/or reaction by-product from the secondhalf-reaction may be purged from the deposition chamber using similarevacuation methods as used for the excess or unreacted species and/orreaction by-product from the first half-reaction.

In some embodiments, providing the base material may include exposingthe plurality of nanoparticles to a first base material precursor at afourth deposition temperature exposure to the plurality of nanoparticlesto a second base material precursor, at a fifth deposition temperature.Exposing of plurality of nanoparticles to the first and second basematerial precursor may be performed in an ALD reaction chamber andtogether comprise an ALD cycle. For example, a plurality ofnanoparticles formed from any suitable substrate material may beprovided and a predetermined number of ALD cycles including exposure tothe first and second base material precursors may be performed todeposit a layer of the base material having a predetermined thicknessthereon, so as to form the plurality of nanostructures that include thebase material. Each of the fourth and fifth deposition temperatures maybe in a range of 100-300 degrees Celsius, inclusive of all ranges andvalues therebetween. In other embodiments, the fourth and fifthdeposition temperatures may be in a range of room temperature to 100degrees Celsius. In some embodiments, a deposition pressure during thefirst and second base material precursor exposures may be in range ofseveral mTorr to 1000 Torr.

In some embodiments, the base material may include Al₂O₃ or any otheraluminum containing base material. In such embodiments, the first basematerial precursor may include an aluminum containing precursorincluding at least one of trimethylaluminum (Al(CH₃)₃) (TMA),triethylaluminum ((C₂H₅)₃Al) (TEA), triethyl(tri-sec-butoxy)dialuminum((C₂H₅)₃Al₂(OC₄H₉)₃), aluminum chloride (AlCl₃), aluminum isopropoxide(Al((OCH(CH₃)₂)₃), dimethylaluminum isopropoxide ((CH₃)₂AlOCH(CH₃)₂),tris(2,2,6,6-tetramethyl-3,5-heptanedionato)aluminum (ARTMHD)₃),tri-isobutylaluminum ((C₄H₉)₃Al), aluminum hexafluoroacetylacetonate(Al(CF₃COCHCOCF₃)₃), aluminum ethoxide (Al(OC₂H₅)₃), aluminum s-butoxide(Al(OC₄H₉)₃), or aluminum acetylacetonate (Al(CH₃COCHCOCH₃)₃).Furthermore, the second base material precursor may include an oxygencontaining precursor such as, for example, at least one of water (H₂O),ozone (O₃), hydrogen peroxide (H₂O₂), or oxygen (O₂). The number ALDcycles of the first and second base material precursors may be selectedbased on a desired thickness of the base material on the nanoparticlesurface.

In other embodiments, the base material may include TiO₂ or any othertitanium containing base material. In such embodiments, the first basematerial precursor may include a titanium containing precursorcomprising at least one of titanium tetraisopropoxide, titaniumtetrachloride, titanium tetraiodide, tetrakis dimethylamino titanium,tetrakis diethylamino titanium, tetrakis ethyl-methylamino titanium,titanium phenyltriisopropoxide, titanocene dichloride, methyltitaniumtrichloride and methyltriisopropoxytitanium, and the second basematerial precursor may include an oxygen containing precursor, aspreviously described herein.

In still other embodiments, the base material may include FeO, Fe₂O₃ orany other iron containing base material. In such embodiments, the firstbase material precursor may include an iron contain precursor, forexample, Fe(Cp)₂FeCl₃, tris(2,2,6,6-tetramethyl-3,5-heptanedionato)Fe(III), or an iron amidinate, and the second base material precursormay include an oxygen containing precursor, as previously describedherein.

In yet other embodiments, the first base material precursor may includediethyl zinc, dimethyl zinc, diphenyl zinc, bis(pentafluorophenyl)zinc,bis(2,2,6,6-tetramethyl-3,5-heptanedionato)zinc(II), tetramethyl tin,molybdenumhexacarbonyl, Bis(cyclopentadienyl)magnesium(II),bis(cyclopentadienyl)zirconium(IV) dihydride 95%, zirconium(IV)dibutoxide(bis-2,4-pentanedionate), zirconium(IV) 2-ethylhexanoate orany other suitable metal containing precursor.

At 104, the plurality of nanostructures are exposed to a first materialat a first deposition temperature, for example, in an ALD reactionchamber. The first deposition temperature may be in a range of 100-300degrees Celsius. A first deposition pressure may be in range of severalmTorr to 1000 Torr. In other embodiments, the first depositiontemperature may be in a range from room temperature to 100 degreesCelsius. In some embodiments, it may be desirable for the boroncontaining composite nanostructure to include aluminum. In suchembodiments, the first material may include an aluminum containingmaterial, which may form a first monolayer of aluminum on the surfacesof the plurality of nanoparticles. In some embodiments, the aluminumcontaining material may be trimethylaluminum (Al(CH₃)₃) (TMA),triethylaluminum ((C₂H₅)₃Al) (TEA), triethyl(tri-sec-butoxy)dialuminum((C₂H₅)₃Al₂(OC₄H₉)₃), aluminum chloride (AlCl₃), aluminum isopropoxide(Al((OCH(CH₃)₂)₃), dimethylaluminum isopropoxide ((CH₃)₂AlOCH(CH₃)₂),tris(2,2,6,6-tetramethyl-3,5-heptanedionato)aluminum (ARTMHD)₃),tri-isobutylaluminum ((C₄H₉)₃Al), aluminum hexafluoroacetylacetonate(Al(CF₃COCHCOCF₃)₃), aluminum ethoxide (Al(OC₂H₅)₃), aluminum s-butoxide(Al(OC₄H₉)₃), or aluminum acetylacetonate (Al(CH₃COCHCOCH₃)₃). Afteroperation 104, any remaining first material is purged from the reactionchamber in which the ALD cycles are being performed, for example, byflowing a suitable inert gas such as argon or nitrogen into the reactionchamber.

In other embodiments, it may be desirable for the boron containingcomposite nanostructure to include titanium. In such embodiments, thefirst material may include a titanium containing precursor comprising atleast one of titanium tetraisopropoxide, titanium tetrachloride,titanium tetraiodide, tetrakis dimethyl amino titanium, tetrakis diethyl amino titanium, tetrakis ethyl-methylamino titanium, titaniumphenyltriisopropoxide, titanocene dichloride, methyltitanium trichlorideand methyltriisopropoxytitanium.

In still other embodiments, it may be desirable for the boron containcomposite nanostructure to include iron (e.g., to obtain a magneticboron containing composite nanostructure). In such embodiments, thefirst material may include Fe(Cp)₂, FeCl₃,tris(2,2,6,6-tetramethyl-3,5-heptanedionato) Fe(III), an iron amidinate,or any other suitable iron containing material.

In yet other embodiments, the first material may include diethyl zinc,dimethyl zinc, diphenyl zinc, bis(pentafluorophenyl)zinc,bis(2,2,6,6-tetramethyl-3,5-heptanedionato)zinc(II), tetramethyl tin,molybdenumhexacarbonyl, Bis(cyclopentadienyl)magnesium(II),bis(cyclopentadienyl)zirconium(IV) dihydride 95%, zirconium(IV)dibutoxide(bis-2,4-pentanedionate), zirconium(IV) 2-ethylhexanoate orany other suitable metal containing material.

At 106, the plurality of nanostructures are exposure to a secondmaterial at a second deposition temperature, for example, in an ALDreaction chamber. For example, the first monolayer formed on the surfaceof each of the plurality of nanoparticles may include a metal and it maybe desirable for the boron containing composite nanostructure to includea metal oxide. In such embodiments, the second precursor materialincludes an oxygen containing material which reacts with the metallicfirst monolayer to form a metal oxide monolayer. In various embodiments,the oxygen containing material may be water (H₂O). In other embodiments,the oxygen containing material may comprise at least one of ozone (O₃),hydrogen peroxide (H₂O₂), or oxygen (O₂). In some embodiments, theoxygen containing material may consist of a first oxygen containingmaterial and the first monolayer may be exposed (e.g., after anintermediate purge cycle), to a second oxygen containing material. Thesecond deposition temperature may be in a range of 100-300 degreesCelsius. In other embodiments, the second deposition temperature may bein a range of room temperature to 100 degrees Celsius. Furthermore, asecond deposition pressure may be in range of several mTorr to 1000Torr. In some embodiments, the metal oxide layer may include the samematerial as the base material. In other embodiments, the metal oxidelayer may be formed from a different material than the base material.After operation 106, any remaining second precursor is purged from thereaction chamber in which the ALD cycles are being performed, forexample, by flowing a suitable inert gas such as argon or nitrogen intothe reaction chamber.

At 108, the plurality of nanostructures are exposed to a ¹⁰B containingmaterial at a third deposition temperature to form ¹⁰B-metal oxide-basedcomposite nanostructure (also referred to herein as “the boron compositenanostructure”), for example, in the ALD reaction chamber. For example,the boron containing material reacts with the metal oxide monolayerformed on the base material to form the boron composite nanostructure.The ¹⁰B containing material may include at least one of boric acid(BH₃O₃), trimethyl borate (TMB) (C₃H₉BO₃), triethyl borate (TEB)(C₆H₁₅BO₃), boron tribromide (BBr₃), boron trifluoride (BF₃), diborontetrafluoride (B₂F₄), triisopropylborane ((C₃H₇)₃B), triethoxyborane((C₂H₅O)₃B), or triisopropoxyborane ((C₃H₇O)₃B). The boron containingmaterials disclosed herein may be enriched with ¹⁰B isotopic elements.The third deposition temperature may be in a range of 100-300 degreesCelsius. In other embodiments, the third deposition temperature may bein a range of room temperature to 100 degrees Celsius. Furthermore, athird deposition pressure may be in range of several mTorr to 1000 Torr.After operation 108, any remaining third precursor is purged from thereaction chamber in which the ALD cycles are being performed, forexample, by flowing a suitable inert gas such as argon or nitrogen intothe reaction chamber.

In some embodiments, the ¹⁰B precursor material may also include a C₁-C₆alcohol compound (e.g., methanol, ethanol, isopropyl alcohol, etc.). Forexample, the ¹⁰Bcontaining material (e.g., a borate or boric acid)dissolved or suspended in the C₁-C₆ alcohol compound, or the ¹⁰Bcontaining material may be introduced into the reaction chambersimultaneously with a C₁-C₆ alcohol compound. In some embodiments, the¹⁰B containing material may be introduced into the reaction chamberprior to the alcohol compound and after purging of the excess firstmaterial and reaction by-product of the first half-reaction. In someembodiments, the ¹⁰B containing material may be introduced into thereaction chamber after the alcohol compound. In some embodiments wherethe C₁-C₆ alcohol compound is present, carbon comprises a minor impurityin the system, with the major component being ¹⁰B in a metal oxide-basematerial composite. In particular embodiments, the C₁-C₆ alcohol mayalso serve as the oxygen containing precursor such that operation 106may be excluded.

In some embodiments, the operation 108 may include a first sub-step ofreacting the first monolayer with the boron containing material followedby purging excess boron containing material and reaction by-product fromthe system and a second sub-step of reacting the boron containingsurface with the oxygen containing precursor followed by purging excessoxygen containing precursor and reaction by-product from the system. Insuch embodiments, operation 106 may be excluded.

In some embodiments, the operation 108 may include a first sub-step ofreacting the oxygen containing surface with the boron containingmaterial, followed by a second sub-step of purging excess oxygencontaining precursor, excess boron containing material, and reactionby-product from the reaction chamber (e.g., by purging the reactionchamber with N₂, argon or any other inert gas). In other embodiments,the operation 108 may include a first sub-step of reacting the firstmonolayer with the boron containing material, followed by a secondsub-step of reacting the boron containing surface with the oxygencontaining material, followed by a third sub-step of purging excessboron containing material, excess oxygen containing material, andreaction by-product from the system. In such embodiments, operation 106may be excluded.

In some embodiments, operations 104, 106, and 108 may be performed anysuitable number of times selected to obtain a desired thickness of the¹⁰B-metal oxide layer on the base material. For example, operations 104,106 and 108 may together form an ALD cycle. In such embodiments, anynumber of ALD cycles may be performed to obtain a desired thickness ofthe ¹⁰B-metal oxide layer on the base material. For example, operations104, 106 and 108 may be repeated a predetermined number of times, at110, to obtain a desired thickness of the ¹⁰B-metal oxide layer on thebase material.

In some embodiments in which the first precursor material includes analuminum containing material, the ¹⁰B-metal oxide-based compositenanostructure comprises ¹⁰B_(x)—Al_(y)O_(z)-base material, where x>0,y>0 and z>0. For example, the boron composite nanostructure may include¹⁰B—AlO-base material or ¹⁰B—Al₂O₃-base material compositenanostructure. In other embodiments, the ¹⁰B-metal oxide-based compositenanostructure includes ¹⁰B_(x)—Al_(2-x)O₃-base material, where x isgreater than 0 and less than 2.

In other embodiments in which the first precursor material includes atitanium containing material, the ¹⁰B-metal oxide-based compositenanostructure comprises ¹⁰B_(x)—Ti_(y)O_(z)-base material, where x>0,y>0 and z>0. For example, the boron composite nanostructure may include¹⁰B—TiO-base material or ¹⁰B—TiO₂-base material.

In some embodiments, the ¹⁰B_(x)—Al_(y)O_(z)-base material may includean oxygen concentration in the range of 40 atomic % to 70 atomic %. Insome embodiments, the ¹⁰B_(x)—Al_(y)O_(z)-base material may comprise anoxygen concentration in the range of 50 atomic % to 60 atomic %. In someembodiments, the ¹⁰B_(x)—Al_(y)O_(z)-base material may comprise analuminum concentration in the range of 15 atomic % to 50 atomic %. Insome embodiments, the ¹⁰B_(x)—Al_(y)O_(z)-base material may comprise analuminum concentration in the range of 25 atomic % to 40 atomic %.Precision-controlled atomic percentage of boron may also be achieved inthe composite films. In some embodiments, the ¹⁰B x-Al_(y)O_(z)-basematerial may comprise a boron concentration in the range of 1 atomic %to 20 atomic %. In some embodiments, the ¹⁰B_(x)—Al_(y)O_(z)-basematerial may comprise a boron concentration in the range of 5 atomic %to 15 atomic %. In the example where x equals 1 (e.g., ¹⁰B—AlO₃ or¹⁰B—Al₂O₃), the boron concentration is 20 atomic %. In some embodiments,the boron concentration may be approximately 40 atomic %.

FIG. 2 is schematic illustration of a ¹⁰B-metal oxide-base materialcomposite nanostructure 200, according to an embodiment. The compositenanostructure 200 comprises a first layer 202 forming a core of thenanostructure 200. The first layer 202 comprises a base material. Insome embodiments, the base material includes at least one of Al₂O₃,Fe₂O₃, ZrO₂, SiO₂, organically modified silica (ORMOSIL), TiO₂, MgO,CaF₂, ZnO, Au, Ag, graphene, graphene oxide, NaCl or KCl, any othersuitable base material or a combination thereof. In particularembodiments, the base material includes a magnetic material (e.g., FeOor Fe₂O₃). In some embodiments, the base material may include a polymer(e.g., a biocompatible polymer such as a biodegradable polymer), forexample, polyamides, polycarbonates, polyurethanes, poly(glycolic acid),polylactides, poly(a-esters), poly(ethylene glycol),poly(lactide-co-glycolide), polyhydroxyalkanoates, polycaprolactones,polypropylene fumarate, polyanhidrides, polyacetals, poly(ortho esters),polycarbonates, polyphosphazenes, polyphosphoesters, polyethers, etc.

The composite nanostructure 200 also comprises a second layer 204 of a¹⁰B-metal oxide composite deposited on the first layer 202 (e.g., viaALD as previously described herein). In some embodiments, the ¹⁰B-metaloxide composite may include a ¹⁰B_(x)—Al_(y)O_(z), where x>0, y>0 andz>0. For example, the second layer 204 may include ¹⁰B—AlO or ¹⁰B—Al₂O₃.In other embodiments, the ¹⁰B-metal oxide-base material compositenanostructure includes ¹⁰B_(x)—Al_(2-x)O₃-base material, where x isgreater than 0 and less than 2. In still other embodiments, the¹⁰B-metal oxide includes ¹⁰B_(x)—Ti_(y)O_(z)-base material, where x>0,y>0 and z>0. For example, the second layer 204 may include ¹⁰B—TiO or¹⁰B—TiO₂.

In some embodiments, any of the ¹⁰B-metal oxide-base material compositenanostructures described herein, for example, having a magnetic basematerial may be used for cancer therapy using boron-neutron capturetherapy (BNCT).

For example, FIG. 3 shows a schematic flow diagram of a method 300 fortreating cancer (e.g., colon cancer, lung cancer, stomach cancer,pancreatic cancer, brain cancer, tumors, cysts, etc.), according to anembodiment. The method 300 includes injecting a plurality of compositenanostructures comprising ¹⁰B-metal oxide-magnetic material compositeinto a blood stream of a patient having cancer cells, at 302. In suchembodiments, the plurality of composite nanostructures may beadministered intravenously into the blood stream of the patient. Inother embodiments, the plurality of composite nanostructures may beadministered orally to the patient. In some embodiments, the ¹⁰B-metaloxide-magnetic material composite may include¹⁰B_(x)—Al_(y)O_(z)—Fe_(a)O_(b) or ¹⁰B_(x)—Ti_(y)O_(z)—Fe_(a)O_(b),where x>0, y>0, z>0, a>0 and b>0. For example, the ¹⁰B_(x)-metaloxide-magnetic material composite may include ¹⁰B—AlO—Fe₂O₃,¹⁰B—Al₂O₃—Fe₂O₃, or ¹⁰B—TiO₂—Fe₂O₃. In other embodiments, the ¹⁰B-metaloxide-base material composite nanostructure includes¹⁰B_(x)—Al_(2-x)O₃—Fe_(a)O_(b), where x is greater than 0 and less than2. The plurality of composite nanostructures may be dissolved orsuspended in an appropriate carrier solution, for example, water, saline(e.g., phosphate buffered saline), biocompatible solvents, or any othersuitable biocompatible carrier solution. In other embodiments in whichoral delivery is desired, the plurality of composite nanostructures maybe compounded in an oral solution, a tablet or a capsule.

In some embodiments, the method 300 also includes incubating theplurality of composite nanostructures within the blood stream of thepatient for a predetermined incubation time, at 304. In variousembodiments, the incubation time may be any suitable time or allowingthe plurality of composite nanostructures to flow through the entirecirculatory system of the patient, so as to allow sufficient time for atleast a portion of the plurality of composite nanostructures to reachthe cancer cells. In particular embodiments, the incubation time mayinclude 10 mins, 20 mins, 40 mins, 1 hour, 2 hours, 3 hours or 4 hoursinclusive of all ranges and values therebetween.

At 306, a magnetic field is generated in a vicinity of the cancer cellsso as to accumulate at least a portion of the plurality of compositenanostructures in the vicinity of the cancer cells. In some embodiments,the magnetic field may be generated by a natural magnet positionedoutside a body of patient proximate to a location of the cancer cells.In other embodiments, an electromagnet (e.g., a probe typeelectromagnet) may be used to generate an electromagnetic field in thevicinity of the cancer cells. In some embodiments, the magnetic fieldmay be maintained in the vicinity of the cancer cells for apredetermined accumulation time (e.g., 10 minutes, 20 minutes, 30minutes, 40 minutes, 50 minutes or 1 hour, inclusive of all ranges andvalues therebetween) so as to allow a larger portion of the plurality ofcomposite nanostructures to accumulate in the vicinity of the cancercells, as the plurality of nanoparticles travel through the circulatorysystem of the patient. In particular embodiments, the incubation timemay be excluded and the accumulation time may be sufficient to allowplurality of nanoparticles to travel through the entire circulatorysystem of the patient as well as accumulation of least a portion of theplurality of composite nanostructures in the vicinity of the cancercells.

At 308, the portion of the composite nanostructures is irradiated with astream of epithermal neutrons. For example, a focused beam of epithermalneutrons is directed to a location of the body of the patient where thecancer cells are located. The epithermal neutrons penetrate the body andirradiate the portion of the plurality of composite nanostructuresaccumulated in the vicinity of the cancer cells. The epithermal neutronsmay react with the ¹⁰B in the composite nanostructures and causegeneration of α particles according to the following equation:

₅ ¹⁰B+₅ ¹ n→ ₅ ¹¹B→₃ ⁷Li+₂ ⁴∝+γ

While the low energy γ particles do not do much damage, the heavy αparticles destroy the cancer cells locally. Beneficially, the heavy αparticles have a penetration distance of only 1-2 cells, thereforelimiting damage to healthy cells located in the proximity of the cancercells. In some embodiments, a mass of ¹⁰B included in the plurality ofcomposite nanostructures is in a range of 20-30 micrograms per gram ofthe cancer cells, which may generate sufficiently heavy α particles todestroy the cancer cells. In particular embodiments, the plurality ofcomposite nanostructures may include ¹⁰B_(x)—Al_(y)O_(z)—Fe₂O₃ or¹⁰B_(x)—Ti_(y)O_(z)—Fe₂O₃, where x>0, y>0, z>0, a>0 and b>0, or¹⁰B_(x)—Al_(2-x)O₃-base material, where x is greater than 0 and lessthan 2, having 350-500 ppm Fe₂O₃ and 20-150 ppm boron.

Experimental Examples

FIG. 4 shows a plot of Quartz Crystal Microbalance (QCM) measurements ofmass deposition using ALD cycles to form a ¹⁰B—AlO composite structureusing a boron containing precursor including ¹⁰Boric Acid-Methanol(¹⁰BA-Methanol) on Si(100) wafer as the base material. TMA was used asan aluminum precursor and water was used as the oxygen containingprecursor. Fast and linear controlled growth of ¹⁰B—AlO is demonstratedup to a mass of about 600 ng/cm². FIG. 5 shows a plot of QCMmeasurements of mass deposition using ALD cycles to form ¹⁰B—AlO filmsusing a boron containing precursor including ¹⁰Trimethyl Borate(¹⁰TMB).Inset shows a scanning electron microscopy (SEM) image of the ¹⁰B—AlOdeposited on Si micropillars to form ¹⁰B—AlO—Si composite micropillars.The micropillars are formed from Si(100) and serve as a substrate fordeposition of the ¹⁰B—AlO composite thereon. Fast and linear controlledgrowth of ¹⁰B—AlO is demonstrated on the QCM surface up to a mass ofabout 850 ng/cm². Table I summarizes various ALD processes to generate¹⁰B—AlO composite layers using ¹⁰BA-Methanol and ¹⁰TMB, and compositionof these layers.

TABLE I Composition of ¹⁰B-AlO layers formed using ALD with a¹⁰BA-Methanol or TMB precursor. Thickness O Al C B Sample ALD Cycle (nm)(atm. %) (atm.%) (atm. %) (atm. %) ¹⁰B-AlO layer formed with ALD cyclesincluding ¹⁰BA-Methanol (¹⁰BAMeOH) boron containing precursor 1 TMA-N₂-24 56.35 29.09 4.49 10.07 BAMeOH-N₂-H₂O-N₂ 2 TMA-N₂-H₂O- 21 57.81 31.642.62 7.92 N₂-BAMeOH-N₂ 3 TMA-N₂- 19 57 28.04 4.78 10.18 BAMeOH-N₂¹⁰B-AlO layer formed with ALD cycles including TMB boron containingprecursor 4 TMA-N₂-H₂O- 20 58.33 30.75 2.3 8.62 N₂-TMB-N₂ 5 TMA-N₂-H₂O-27 57.97 27.65 1.83 12.54 TMB-N₂

FIG. 6A is an optical image of Al₂O₃ nanoparticles; FIGS. 6B, 6C and 6Dare optical images of the Al₂O₃ nanoparticles coated with iron oxideusing progressive ALD cycles of Fe(Cp)₂ as an iron containing precursorand O₃ as an oxygen containing precursor so as to coat the Al₂O₃nanoparticles with a layer of Fe₂O₃ and form magnetic nanoparticles. ALDcan be used to control the thickness of the Fe₂O₃ layer on the Al₂O₃base layer. FIGS. 7A-7L are SEM images at various magnifications of theFe₂O₃ coated Al₂O₃ nanoparticles formed using the ALD process.

FIG. 8A is an X-ray Photon Spectroscopy (XPS) plot showing compositionof commercially available Fe₂O₃ nanoparticles, and FIG. 8B is an XPSplot of composition of B—AlO—Fe₂O₃ composite nanostructures formed fromthe commercially available Fe₂O₃ nanoparticles using ALD. Thecommercially available Fe₂O₃ particles had a diameter in a range of20-40 nm. Thirty ALD cycles of TMA and ¹⁰BA-methanol were performed at200 degrees Celsius to coat the Fe₂O₃ nanoparticles with about a 2.8 nmthick ¹⁰B—AlO layer to form ¹⁰B—AlO—Fe₂O₃ composite nanostructures. Theratio of Al to ¹⁰B was 3.1. FIG. 9A is an XPS plot in the Boron spectrumof the commercially available Fe₂O₃ nanoparticles, and FIG. 9B is an XPSplot in the Boron spectrum of the ¹⁰B—AlO—Fe₂O₃ compositenanostructures. A visible ¹⁰B peak is observed after performing the¹⁰B—AlO ALD on the Fe₂O₃ nanoparticles. Table II summarizes compositionof the commercially available Fe₂O₃ nanoparticles before and after theALD process.

TABLE II Composition of commercially available Fe₂O₃ nanoparticles and¹⁰B—AlO—Fe₂O₃ composite nanostructures formed therefrom using ALD.Element Atomic % Fe₂O₃ Al 0 B 0 C 4.16 O 57.64 Fe 38.2 ¹⁰B—AlO—Fe₂O₃ Al13.85 B 4.41 C 4.86 O 62.45 Fe 14.41

FIG. 10 is an optical image of ¹⁰B—AlO—Fe₂O₃ composite nanostructuresformed by performing a 2 second TMA exposure, a 20 second N₂ purge, a 2second ¹⁰B A-MeOH exposure and a 20 second N₂ purge. A total of 50cycles were performed obtain an about 5 nm thick ¹⁰B—AlO layer on theFe₂O₃ nanoparticles as observed on a Si monitor wafer present in thereaction chamber during the ALD process. FIGS. 11A, 11B and 11C are XPSscans in the aluminum, boron and oxygen spectrums, respectively of theB—AlO—Si composite nanostructures. FIGS. 12A, 12B, 12C and 12D are XPSscans in the aluminum, boron, oxygen and iron spectrums, respectively ofthe B—AlO—Fe₂O₃ composite nanostructures of FIG. 10. ¹⁰B peaks areclearly observed in FIGS. 11B and 12B.

As used herein, the singular forms “a”, “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, the term “a member” is intended to mean a single member or acombination of members, “a material” is intended to mean one or morematerials, or a combination thereof.

As used herein, the terms “about” and “approximately” generally meanplus or minus 10% of the stated value. For example, about 0.5 wouldinclude 0.45 and 0.55, about 10 would include 9 to 11, about 1000 wouldinclude 900 to 1100.

It should be noted that the term “exemplary” as used herein to describevarious embodiments is intended to indicate that such embodiments arepossible examples, representations, and/or illustrations of possibleembodiments (and such term is not intended to connote that suchembodiments are necessarily extraordinary or superlative examples).

It is important to note that the construction and arrangement of thevarious exemplary embodiments are illustrative only. Although only a fewembodiments have been described in detail in this disclosure, thoseskilled in the art who review this disclosure will readily appreciatethat many modifications are possible (e.g., variations in sizes,dimensions, structures, shapes and proportions of the various elements,values of parameters, mounting arrangements, use of materials, colors,orientations, etc.) without materially departing from the novelteachings and advantages of the subject matter described herein. Othersubstitutions, modifications, changes and omissions may also be made inthe design, operating conditions and arrangement of the variousexemplary embodiments without departing from the scope of the presentinvention.

While this specification contains many specific implementation details,these should not be construed as limitations on the scope of anyembodiments or of what may be claimed, but rather as descriptions offeatures specific to particular implementations of particularembodiments. Certain features described in this specification in thecontext of separate implementations can also be implemented incombination in a single implementation. Conversely, various featuresdescribed in the context of a single implementation can also beimplemented in multiple implementations separately or in any suitablesubcombination. Moreover, although features may be described above asacting in certain combinations and even initially claimed as such, oneor more features from a claimed combination can in some cases be excisedfrom the combination, and the claimed combination may be directed to asubcombination or variation of a subcombination.

What is claimed is:
 1. A method, comprising: providing a plurality ofnanostructures comprising a base material; exposing the plurality ofnanostructures to a first material at a first deposition temperature;exposing the plurality of nanostructures to a second material at asecond deposition temperature; and exposing the plurality ofnanostructures to a Boron-10 (¹⁰B) containing material at a thirddeposition temperature so as to form ¹⁰B-metal oxide based compositenanostructures.
 2. The method of claim 1, wherein the first material isan aluminum containing material comprising at least one oftrimethylaluminum (Al(CH₃)₃) (TMA), triethylaluminum ((C₂H₅)₃Al) (TEA),triethyl(tri-sec-butoxy)dialuminum ((C₂H₅)₃Al₂(OC₄H₉)₃), aluminumchloride (AlCl₃), aluminum isopropoxide (Al((OCH(CH₃)₂)₃),dimethylaluminum isopropoxide ((CH₃)₂AlOCH(CH₃)₂),tris(2,2,6,6-tetramethyl-3,5-heptanedionato)aluminum (Al(TMHD)₃),tri-isobutylaluminum ((C₄H₉)₃Al), aluminum hexafluoroacetylacetonate(Al(CF₃COCHCOCF₃)₃), aluminum ethoxide (Al(OC₂H₅)₃), aluminum s-butoxide(Al(OC₄H₉)₃), or aluminum acetylacetonate (Al(CH₃COCHCOCH₃)₃).
 3. Themethod of claim 2, wherein the ¹⁰B-metal oxide based compositenanostructure comprises ¹⁰B_(x)—Al_(y)O_(z)-base material, where x>0,y>0 and z>0.
 4. The method of claim 1, wherein the first material is atitanium containing material comprising at least one of titaniumtetraisopropoxide, titanium tetrachloride, titanium tetraiodide,tetrakis dimethylamino titanium, tetrakis diethylamino titanium,tetrakis ethyl-methylamino titanium, titanium phenyltriisopropoxide,titanocene dichloride, methyltitanium trichloride ormethyltriisopropoxytitanium.
 5. The method of claim 4, wherein the¹⁰B-metal oxide based composite nanostructure comprises¹⁰B_(x)—Ti_(y)O_(z)-base material, where x>0, y>0 and z>0.
 6. The methodof claim 1, wherein the ¹⁰B containing material comprises at least oneof boric acid (BH₃O₃), trimethyl borate (TMB) (C₃H₉BO₃), triethyl borate(TEB) (C₆H₁₅BO₃), boron tribromide (BBr₃), boron trifluoride (BF₃),diboron tetrafluoride (B₂F₄), triisopropylborane ((C₃H₇)₃B),triethoxyborane ((C₂H₅O)₃B), or triisopropoxyborane ((C₃H₇O)₃B).
 7. Themethod of claim 6, wherein the ¹⁰B containing material also comprises aC₁-C₆ alcohol compound.
 8. The method of claim 7, wherein the C₁-C₆alcohol compound comprises methanol.
 9. The method of claim 1, whereineach of the first deposition temperature, the second decompositiontemperature and the third deposition temperature is in a range of100-300 degrees Celsius.
 10. The method of claim 1, wherein the basematerial comprises one of Al₂O₃, FeO, Fe₂O₃, ZrO₂, SiO₂, organicallymodified silica (ORMOSIL), TiO₂, MgO, CaF₂, ZnO, Au, Ag, graphene,graphene oxide, NaCl or KCl.
 11. The method of claim 9, whereinproviding the plurality of nanostructures comprises: exposing aplurality of nanoparticles to a first base material precursor at afourth deposition temperature; and exposing the plurality ofnanoparticles to a second base material precursor at a fifth depositiontemperature, wherein a layer of the base material is deposited on eachof the plurality of nanoparticles.
 12. A composite nanostructure,comprising: a first layer forming a core of the composite nanostructure,the first layer comprising a base material; and a second layer of a¹⁰B-metal oxide composite deposited on the first layer.
 13. Thecomposite nanostructure of claim 12, wherein the ¹⁰B-metal oxidecomposite comprises ¹⁰B_(x)—Al_(y)O_(z), where x>0, y>0 and z>0.
 14. Thecomposite nanostructure of claim 12, wherein the ¹⁰B-metal oxidecomposite comprises ¹⁰B_(x)—Ti_(y)O_(z)-base material, where x>0, y>0and z>0.
 15. The composite nanostructure of claim 12, wherein the basematerial comprises one of Al₂O₃, FeO, Fe₂O₃, ZrO₂, SiO₂, organicallymodified silica (ORMOSIL), TiO₂, MgO, CaF₂, ZnO, Au, Ag, graphene,graphene oxide, NaCl or KCl.
 16. The composite nanostructure of claim15, wherein the base material is a magnetic material.
 17. A method oftreating cancer, comprising: injecting a plurality of compositenanostructures comprising ¹⁰B-metal oxide-magnetic material, into ablood stream of a patient having cancer cells; generating a magneticfield in a vicinity of the cancer cells so as to accumulate at least aportion of the plurality of composite nanostructures in the vicinity ofthe cancer cells; and irradiating the portion of the compositenanostructures with a stream of epithermal neutrons.
 18. The method ofclaim 17, further comprising: prior to generating the magnetic field,incubating the plurality of composite nanostructures within the bloodstream of the patient for a predetermined incubation time.
 19. Themethod of claim 17, wherein the ¹⁰B_(x)-metal oxide-magnetic materialcomprises ¹⁰B_(x)—Al_(y)O_(z)—Fe_(a)O_(b) or¹⁰B_(x)—Ti_(y)O_(z)—Fe_(a)O_(b), where x>0, y>0, z>0, a>0 and b>0. 20.The method of claim 17, wherein a mass of ¹⁰B included in the pluralityof composite nanostructures is in a range of 20-30 micrograms per gramof the cancer cells.